This invention relates to a process for preparing 4-hydroxy-3-methoxyphenylacetone which is an intermediate for the important antihypertensive agent, methyldopa.
The use of 4-hydroxy-3-methoxyphenylacetone in the methyldopa synthesis has been disclosed in U.S. Pat. No. 2,868,818 which comprises (1) the addition of a cyanide anion to 4-hydroxy-3-methoxyphenylacetone to form 4-methyl-4-(4-hydroxy-3-methoxybenzyl)hydantoin; (2) basic hydrolysis of the hydantoin to afford .alpha.-methyl-.beta.-(4-hydroxy-3-methoxyphenyl)alanine; and (3) subsequent hydrolysis with hydrobromic acid to form methyldopa, i.e., .alpha.-methyl-.beta.-(3,4-dihydroxyphenyl)alanine.
Presently, 4-hydroxy-3-methoxyphenylacetone is manufactured from vanillin and nitroethane (Pearl et al, J. Org. Chem., 16, p. 221, 1951). The process suffers from the high cost of vanillin and a sole supplier for nitroethane.
For these reasons, an alternate synthesis of 4-hydroxy-3-methoxyphenylacetone is desirable to safeguard the continuous production of methyldopa.
The novel process of this invention comprises three steps:
(1) formation of a 1,1-di(4-hydroxy-3-methoxyphenyl)-2-alkoxypropane (I) (diguaiacyl-2-alkoxypropane) from reacting two moles of 1-hydroxy-2-methoxybenzene (guaiacol) and one mole of 2-alkoxypropanal; and
(2) basic elimination of compound (I) to form the enol ether of 4-hydroxy-3-methoxyphenylacetone; and
(3) conversion to the parent phenylacetone upon treatment with strong acid.
The acid catalyzed condensation between guaiacol and unsubstituted propanal is known (German Pat. No. 2,418,973). According to the German patent, the resulting 1,1-diguaiacylpropane undergoes thermal cleavage to afford 1-guaiacylpropene in the presence of a basic catalyst. However, the German patent does not suggest the present invention because it is well known in the art that .alpha.-oxy-substituted aldehydes such as .alpha.-acetoxy or .alpha.-methoxypropanal behave differently from unsubstituted propanal such as used in the German patent. As shown below, an .alpha.-oxy-substituted aldehyde has a great tendency to eliminate the oxy function under acidic conditions. ##STR1## Furthermore, the notorious ability of the resulting acrylaldehyde to polymerize would have led to the expectation that the guaiacol-propanal condensation would not be extrapolated to .alpha.-oxysubstituted aldehydes due to the latter's superseding decomposition rate. This expectation has actually been realized by the failure of .alpha.-acetoxypropanal to react with guaiacol at all. Instead, acetic acid is eliminated and the resulting acrylaldehyde polymerizes as expected.
Therefore, it is totally unexpected that .alpha.-alkoxypropanal would condense with guaiacol under acid catalysis to yield the desired diguaiacyl-2-alkoxypropane.
Accordingly, it is an object of the present invention to provide a new, alternate process for the production of 4-hydroxy-3-methoxyphenylacetone.
It is also an object of this invention to provide a process which is economically more advantageous than the current manufacturing process based on vanillin.
Still another object of the present invention is to provide the novel 1,1-diguaiacyl-2-alkoxypropanes as useful intermediates for 4-hydroxy-3-methoxyphenylacetone.